HDLs in crises

Eckardstein, Arnold von; Rohrer, Lucia

doi:10.1097/mol.0000000000000294

Cited by 31 publications

(15 citation statements)

References 107 publications

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“…In conclusion, the data reported here support the role of Arg123 of apoA-I in transacylation of fatty acids produced by LCAT phospholipid hydrolysis to cholesterol. This novel mechanistic view on the function of apoA-I as LCAT activator on nascent (discoidal) HDL may be helpful for better understanding the mechanisms of disorders involving "dysfunctional" HDL and abnormal LCAT activity (1,8,55,56).…”

Section: Discussionmentioning

confidence: 99%

Arginine 123 of apolipoprotein A-I is essential for lecithin:cholesterol acyltransferase activity

Gorshkova

Mei

Atkinson

2018

Journal of Lipid Research

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ApoA-I activates LCAT that converts lipoprotein cholesterol to cholesteryl ester (CE). Molecular dynamic simulations suggested earlier that helices 5 of two antiparallel apoA-I molecules on discoidal HDL form an amphipathic tunnel for migration of acyl chains and unesterified cholesterol to the active sites of LCAT. Our recent crystal structure of Δ(185-243)apoA-I showed the tunnel formed by helices 5/5, with two positively charged residues arginine 123 positioned at the edge of the hydrophobic tunnel. We hypothesized that these uniquely positioned residues Arg123 are poised for interaction with fatty acids produced by LCAT hydrolysis of the sn-2 chains of phosphatidylcholine, thus positioning the fatty acids for esterification to cholesterol. To test the importance of Arg123 for LCAT phospholipid hydrolysis and CE formation, we generated apoA-I[R123A] and apoA-I[R123E] mutants and made discoidal HDL with the mutants and WT apoA-I. Neither mutation of Arg123 changed the particle composition or size, or the protein conformation or stability. However, both mutations of Arg123 significantly reduced LCAT catalytic efficiency and the apparent for CE formation without affecting LCAT phospholipid hydrolysis. A control mutation, apoA-I[R131A], did not affect LCAT phospholipid hydrolysis or CE formation. These data suggest that Arg123 of apoA-I on discoidal HDL participates in LCAT-mediated cholesterol esterification.

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Section: Discussionmentioning

confidence: 99%

Arginine 123 of apolipoprotein A-I is essential for lecithin:cholesterol acyltransferase activity

Gorshkova

Mei

Atkinson

2018

Journal of Lipid Research

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“…CETP inhibition probably also extends the lifespan of dysfunctional HDL. This may not only eliminate the postulated atheroprotective effect but even be harmful if HDL gained adverse properties [ 9 , 74 , 108 ]. Future strategies may include the identification of patients who benefit from CETP inhibition.…”

Section: Should Hdl-c Be Increased By Therapeutic Measures?mentioning

confidence: 99%

HDL cholesterol: reappraisal of its clinical relevance

et al. 2017

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BackgroundWhile several lines of evidence prove that elevated concentrations of low-density lipoproteins (LDL) causally contribute to the development of atherosclerosis and its clinical consequences, high-density lipoproteins are still widely believed to exert atheroprotective effects. Hence, HDL cholesterol (HDL-C) is in general still considered as “good cholesterol”. Recent research, however, suggests that this might not always be the case and that a fundamental reassessment of the clinical significance of HDL-C is warranted.MethodThis review article is based on a selective literature review.ResultsIn individuals without a history of cardiovascular events, low concentrations of HDL-C are inversely associated with the risk of future cardiovascular events. This relationship may, however, not apply to patients with metabolic disorders or manifest cardiovascular disease. The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion. These roles in cholesterol metabolism as well as many other biological functions of HDL particles are dependent on the number as well as protein and lipid composition of HDL particles. They are poorly reflected by the HDL-C concentration. HDL can even exert negative vascular effects, if its composition is pathologically altered. High serum HDL-C is therefore no longer regarded protective. In line with this, recent pharmacological approaches to raise HDL-C concentration have not been able to show reductions of cardiovascular outcomes.ConclusionIn contrast to LDL cholesterol (LDL-C), HDL-C correlates with cardiovascular risk only in healthy individuals. The calculation of the ratio of LDL-C to HDL-C is not useful for all patients. Low HDL-C should prompt examination of additional metabolic and inflammatory pathologies. An increase in HDL-C through lifestyle change (smoking cessation, physical exercise) has positive effects and is recommended. However, HDL-C is currently not a valid target for drug therapy.

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“…In addition, HDL are known to exert beneficial effects on endothelial cells, including the stimulation of nitric oxide (NO) production, the inhibition of the apoptotic action of stimuli such as TNF-α and oxidized LDL, and the promotion of cell proliferation and migration [6, 7]. However, recent results from genetic or clinical research have cast considerable doubt on the relevance of increasing HDL-C concentration per se [8]. First, Mendelian randomization studies of common genetic variants for HDL-C are inconsistent in their support for a causal relationship between HDL-C concentration and cardiovascular diseases [9, 10].…”

Section: Introductionmentioning

confidence: 99%

“…First, Mendelian randomization studies of common genetic variants for HDL-C are inconsistent in their support for a causal relationship between HDL-C concentration and cardiovascular diseases [9, 10]. Second, in clinical trials, HDL-C raising drugs, such as nicotinic acid and CETP inhibitors, have failed to reduce cardiovascular events any more than statins administered alone [8, 11]. One argument to explain these discrepancies is that assessment solely on HDL-C might not predict the outcome of pharmacological intervention.…”

Section: Introductionmentioning

confidence: 99%

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Castaing-Berthou¹,

Malet²,

Radojkovic³

et al. 2017

Cell Physiol Biochem

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Background/Aims: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F₁-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F₁-ATPase activation. Methods: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F₁-ATPase activation by apoA-I. Results: ApoA-I and HDL both induced Akt phosphorylation. F₁-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F₁-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y₁-ADPreceptor and the PI3Kβ isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. Conclusion: Altogether, these data highlight a key role of the P2Y₁/PI3Kβ axis in endothelial cell proliferation downstream of ecto-F₁-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.

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HDLs in crises

Cited by 31 publications

References 107 publications

Arginine 123 of apolipoprotein A-I is essential for lecithin:cholesterol acyltransferase activity

Arginine 123 of apolipoprotein A-I is essential for lecithin:cholesterol acyltransferase activity

HDL cholesterol: reappraisal of its clinical relevance

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

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